Esterification of 17alpha-ethinyl-17beta-hydroxy steroids



United States Patent 3,403,371 ESTERiFICATION 0F 17cc-ETHINYL-17fi-HYDROXY STERGZDS @tto Haipcrn, Palo Alto, Calif., assignor to SyntaxCorporation, Panama, Panama, a corporation of Panama No Drawing. FiledJune 16, 1966, Ser. No. 557,835 10 (Ilainas. (Cl. ass-e974) Thisinvention relates to a new and novel process for the esterification ofcyclopentanophenanthrene derivatives.

Many of the esterified hydroxy steroids of the androstane and estraneseries are recognized to be of therapeutic value, including theesterified steroids with free keto groups. For example,l7a-ethynyl-l7B-acetoxyestr-4-en- 3-one has been shown to be aneffective progrestationa'l agent, and l7fi-propoxyandrost-4-en-3-one hasbeen shown to be an effective androgenic and anabolic agent.

Hydroxy steroids are generally esterified with the assistance of acatalyst. The primary and secondary hydroxy groups can be esterified inthe presence of an acid catalyst,

such as hydrogen chloride, or a basic catalyst, such as pyridine; buttertiary hydroxy groups are generally only esterifiable in the presenceof an acid catalyst. However, under such conditions, enolizable ketogroups are also esterified. Hence, when an esterified tertiary hydroxysteroid with free keto groups is desired, a selective hydrolysis of theenol ester is required subsequent to the esterification. For example,the preparation of 17B-acetoxy-l7u-methylestr-4-en-3-one requires twosteps: first, 17 3-hydroxy-l7a-methylestr-4-en-3-one is esterified withacetic anhydride in the presence of an acid catalyst, such asp-toluenesulfonic acid, and second, the resulting 3,175-diacetoxy-l7a-methylestra-3,5-diene is selectively hydrolyzed to yieldthe desired product.

The process of the present invention permits the complete esterificationof hydroxy steroids without the necessity of using a catalyst. And,further, by practicing the procedure of the present invention, theacyloxy esters of hydroxy steroids are prepared directly without theformation of enol esters. For example,17B-acetoxy-17u-ethynylestr-4-en-3-one is prepared directly from17,6-hydroXy-l7- ethynylestr-3-en-3-one in one step. Another outstandingfeature of this process is that it permits complete esterification inhigh yields, e.g., yields of 90% or more.

It is to be understood that for purposes of the present invention, acidanhydrides are the homologous, simple anhydrides of hydrocarboncarboxylic acids, the acyl groups of which will contain less than 12carbon atoms and have a straight, branched, cyclic or cyclic-aliphaticchain structure. This structure may be saturated, unsaturated, oraromatic, and optionally substituted by functional groups, such asalkyloxy containing up to carbon atoms, halogeno, and the like. Typicalanhydrides thus include: acetic, propionic, enanthic, caproic,trirnethylacetic, t-butylacetic, cyclopentylpropionic,fl-chloropropicnic, dichloroacetic anhydride, and the like.

The process, as said above, requires no catalyst. In fact, for theprocess to be effective, the reaction mixture must be substantially freeof any acid, such as mineral acids like sulfuric acid, or halogen acidslike hydrochloric acids, or carboxylic acids like acetic acid, orsulfonic acids like p-toluenesulfonic acid, or the like. For thisreason, the acid anhydride used in this reaction must be substantiallyfree of acids. The acid anhydrides can be purified by conventionaltechniques, such as fractional distillation. If a' technical grade ofacid anhydride is to be used, the acid anhydride should first bedistilled from sodium acetate to remove any minerals or halogenspresent, then the technical grade acid anhydride is fractionallydistilled if necessary.

The process of the present invention comprises treating the hydroxysteroid with at least a 5-molar excess, and

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preferably about a 25 to about a IOU-molar excess per hydroxy group, ofthe appropriate acid anhydride; larger excesses of acid anhydride arepractical and can also be used if desired. Optionally, a nonaqueous,inert, organic solvent is used in conjunciton with the acid anhydride inamounts of about one-half to about twice the volume of the acidanhydride used. The use of the inert solvent can be foregone if desired,as the process is equally eflicient using either the acid anhydridealone or in conjunction with an inert solvent.

The resulting mixture, which is composed of the steroid, the reagent,and optionally the solvent, is heated so as to permit removal of some ofthe mixture by distillation. The mixture is distilled off at a rateequal to about 1% to about 25%, and preferably about 2% to about 10%, ofthe original reaction mixture volume per hour. However, the rate must beat least such that any acid that is formed during the reaction issubstantially removed by distillation as rapidly as it is formed. Thedistillation is continued for a period of time ranging from about 1 toabout 48 hours or longer. The period of distillation will vary,dependent on various factors such as the difliculty of the particularesterification, the particular acid anhydride used, the particular inertsolvent, if any, that is used, the particular steroid being esterified,and so forth.

If the distillation is vigorous and rapid, or continued for a prolongedperiod of time, additional amounts of acid anhydride and/or solvent canbe added during the course of the distillation to maintain the reactionvolume. The isolation, purification and yield of the esterified steroidare improved if the reaction volume is maintained at least at one-thirdof its total initial volume, preferably at more than one-half of thetotal initial volume.

Any nonaqueous, inert, organic solvent or combinations of such solventscan be used in this process, but the solvent employed is generallyselected so as to have a lower boiling point or range than that of theacid anhydride, and preferably the solvent will have a boiling point orrange above that of any carboxylic acid that will be formed during thereaction. Typical examples of such solvents are: benzene, toluene,xylenes, cymenes, cumenes, durene, hexanes, decanes, dioxane,cyclohexane, naphthalene, l-methylnaphthalene, and so forth. Any ofthese solvents can be combined to form an organic solvent system, e.g.,a xylene solvent composed of ortho, meta and para-xylenes, or anaromatic solvent composed of benzene and toluene in any proportions.

At the completion of the process, the steroid is isolated and purifiedaccording to conventional techniques. For example, ice water is added tothe cooled reaction mixture to decompose the excess anhydride, and themixture is steam distilled to remove the solvent. The ester steroid maythen be isolated by salting it out with the addition of an inorganicsalt and collected by filtration. It is then dissolved in an inert,organic solvent which is nonmiscible with water, and washed with anaqueous basic solution and with water to neutrality. The solution isdried and evaporated to dryness to yield the esterified steroid. Ifnecessary, the steroid can be further purified by conventionaltechniques, such as chromatography, recrystallization, and so forth.

Typical hydroxy steroids that can be completely esterified by thisprocess are:

l7B hydroxyandrost-4-en-3-one, l7fl-hydroxyestr-4-en-3-one,17fi-hydroxy-17a-ethynylestr-4-en-3-0ne, 10,8,173-dihydroxyandrost-4-en-3-one,

3 ,6, l -dihydroxyestral ,3,5 10) -triene,

3B, 16,8,17,8-trihydroxyestra-1,3,5( 10) -triene,6wmethyl-17a-ethynyl-l7B-hydroxyestr-4-en-3-one, 6-chlorol 7a-ethynyll7/i-hydroxyestra-4, 6-dien-3 -one,

3 17 a-ethynyl- 17 fi-hydroxyestr-S 10) -en-3 -on 2a,3tx-isopropyliden-l 7a-ethynyll7fi-hydroxyestrane, 17a-ethynyl- 17fi-hydroxyandrostl-ene, 17a-ethynyl-l 75-hydroxyestr-4-ene,17a-ethynyll7fi-hydroxyandrost-4en-3 one,

and so forth. Of the hydroxy steroids, the 17-hydroxy-17- ethynylsteroids of the androstane and estrane series are the preferred startingmaterials for this process.

In order that those skilled in the art will more fully understand theprocess of the present invention, the following examples are provided asillustrations. In no way are these examples to be construed aslimitations of the present invention.

EXAMPLE 1 One-hundred grams of Hot-ethynyl-17fl-hydroxyestr-4- en-3-oneare added to a solution of l l. of xylene and 11. of aceticanhydride..The resulting mixture is distilled at such a rate so as 450m1. of distillate will be collected within a period of 8 hours. Theremaining reaction mixture is added to 3 l. of water and the resultingmixture is steam distilled until no more xylene is removed. Sodiumchloride is added and the material that is salted out is collected byfiltration. The filtered solid is dissolved in ethyl acetate and washedwith an aqueous solution of sodi-um bicarbonate and water to neutrality.The ethyl acetate solution is dried and evaporated to dryness to give17wethynyl-17/8-acetoxyestr-4-en-3-one. The melting point range is163-164 C. and the actual yield is 96% of theoretical yield.

EXAMPLE 2 By using the same procedure as described in Example 1, butusing 17a-ethynyl-l7/3-hydroxyandrost-4-en-3-one as the starting hydroxysteroid, flat-ethynyl-17fi-acetoxyandrost-4-en-3-one is formed.

EXAMPLE 3 To a solution consisting of 500 ml. of xylene and 500 ml. ofacetic anhydride, 10 g. of 17u-ethynyl-176-hydroxyestr-(10)-en-3-one isadded. The mixture is distilled for 12 hours at such a rate so as 25 ml.of distillate are distilled over per hour. At the completion ofdistillation, 2 l. of ice water are cautiously added to the cooledreaction mixture, and the resulting mixture is steam distilled untilsubstantially all the xylene has been removed. The solid that forms uponthe addition of sodium chloride is collected by filtration, washed withwater, then dissolved in a liter of methylene chloride. The resultingmixture is washed with an aqueous solution of sodium carbonate and waterto neutrality, dried and evaporated to dryness, yielding17a-ethynyl-175-acetoxyestr-5 -en-3-one.

EXAMPLE 4 One gram of 6-chloro-17a-ethynyl-17B-hydroxyestra-4,6-dien-3-one is added to a solution consisting of 10 ml. of xylene and10 m1. of acetic anhydride. The solution is heated and distilled for 8hours; during this period, 8 ml. of distillate is collected. At thecompletion of the reaction the mixture is added to 20 ml. of water. Thismixture is extracted with methylene chloride, and these extracts arewashed with an aqueous solution of potassium bicarbonate and water toneutrality, dried and evaporated to dryness to yield6-chloro-17a-ethynyl-17fi-acetoxyestra-4,6-dien-3- one.

EXAMPLE 5 Using the same procedure as set forth in Example 4, bututilizing 18 m1. of caproic anhydride in place of 10 ml. of aceticanhydride and using g. of naphthalene in place of 10 ml. of xylene,6-chloro-17a-ethyny1-17,9-caproxyestra-6-dien-3-one is formed.

EXAMPLE 6 Using the same procedure as described in Example 4, butreplacing the 10 ml. of acetic anhydride with 15 ml.

of propionic anhydride and replacing the 10 m1. of xylene with 10 ml. ofcumene and using 6m-methyl-17a-ethylnyl- 17 8-hydroxyestr-4-en-3-one asthe starting hydroxy steroid, 6a methyl 17a ethynyl 17 8 propionoxyestr4 en- 3-one is formed.

EXAMPLE 7 Three thousand and twenty grams ofl7ot-ethynyl-l7fihydroxyestr-4-en-3-one are added to a solutionconsisting of 50 l. of xylene and50 l. of acetic anhydride. Theresulting mixture is heated and 10 l. of the mixture are distilled olfhourly. After 4 hours of distillation, the reaction mixture isreplenished with hourly additions of 5 l. of xylene and 5 l. of aceticanhydride. The distillation is continued for another 7 hours.One-hundred and twenty liters of water are added to the cooled mixture,and the mixture is then steam distilled until all the xylene has beenremoved from the mixture. The steroid is salted out with the addition ofsodium chloride; the solid steroid-is filtered oif and washed withwater. The solid is placed-in methyl ene chloride and washed withaqueous sodium carbonate and water to neutrality, dried, and evaporatedto dryness to yield 17a-ethylnyl-17fi-acetoxyestr-4-en-3-one.

What is claimed is:

1. A process for the esterification of 17fi-hydroxy-17aethynyl steroidswhich comprises treating the steroid with at least a 5-molar excess ofan anhydride of a hydrocarbon carboxylic acid at a temperaturesuificient to permit removal by distillation of the acid that is formed.

2. The process according to claim 1 wherein the steroid is treated withabout a 25 to about a -molar excess of an anhydride of a hydrocarboncarboxylic acid.

3. The process according to claim 1 wherein the compound is treated withan anhydride of a hydrocarbon carboxylic acid in an inert media whosevolume is about onehalf to about twice the volume of the acid anhydrideused.

4. The process according to claim 1 wherein the distillation rate isfrom about 1% to about 10% of the initial reaction mixture volume perhour.

5. The process according to claim 1 wherein the distillation rate issufficient to remove any carboxylic acid formed during the process asrapidly as it is formed.

6. The process according to claim 1 wherein the hydrocarbon carboxylicacid anhydride is selected from a group consisting of acetic anhydride,propionic anhydride, and caproic anhydride.

7. The process according to claim 1 wherein the compounds are17z-ethynyl-17 3-hydroxy steroids of the androstane and estrane series.

8. The process according to claim 1 wherein the 17,8-hydroxy-17a-ethynyl steroids are treated in the absence of any acid withabout a 25 to about a lOO-molar excess of an anhydride of a hydrocarboncarboxylic acid in an inert media having a volume of about one-half toabout twice that of the hydrocarbon carboxylic acid anhydride used,while continuously distilling ofi" some of the reaction mixture at asufiicient rate so as to substantially all carboxylic acid is removed asrapidly as it is formed in the reaction mixture.

9. The process according to claim 1 wherein the 17,8-hydroxy-17a-ethyny1 steroid is l7a-8lll1Yl'1Yl-17fi-l'lYdIOXestr-4-en-3-one.

10. The process according to claim 1 wherein the 17,8-hydroxy-17ot-ethynyl steroid is 17a-ethynyl-17fi-hydroxyestr-510)-en-3-one.

References Cited UNITED STATES PATENTS 2,838,500 6/1958 Campbell et al.260-239.55

LEWIS GOTTS, Primary Examiner.

E. G. LOVE, Assistant Examiner.

1. A PROCESS FOR THE ESTERIFICATION OF 17B-HYDROXY-17AETHYNYL STEROIDSWHICH COMPRISES TREATING THE STEROID WITH AT LEAST A 5-MOLAR EXCESS OFAN ANHYDRIDE OF A HYDROCARBON CARBOXYLIC ACID AT A TEMPERATURE SUFFICIENT TO PERMIT REMOVAL BY DISTILLATION OF THE ACID THAT IS FORMED.
 9. THEPROCESS ACCORDING TO CLAIM 1 WHEREIN THE 17BHYDROXY-17A-ETHYNYL STEROIDIS 17A-ETHYNYL-17B-HYDROXYESTR-4-EN-3-ONE.